Endothelial cells-derived SEMA3G suppresses glioblastoma stem cells by inducing c-Myc degradation

Peng Xiang Min; Li Li Feng; Yi Xuan Zhang; Chen Chen Jiang; Hong Zhen Zhang; Yan Chen; Kohji Fukunaga; Fang Liu; Yu Jie Zhang; Takuya Sasaki; Xu Qian; Katsuhisa Horimoto; Jian Dong Jiang; Ying Mei Lu; Feng Han

doi:10.1038/s41418-025-01534-3

Endothelial cells-derived SEMA3G suppresses glioblastoma stem cells by inducing c-Myc degradation

Peng Xiang Min, Li Li Feng, Yi Xuan Zhang, Chen Chen Jiang, Hong Zhen Zhang, Yan Chen, Kohji Fukunaga, Fang Liu, Yu Jie Zhang, Takuya Sasaki, Xu Qian, Katsuhisa Horimoto, Jian Dong Jiang, Ying Mei Lu, Feng Han

PHA - Life and Pharmaceutical Science

Research output: Contribution to journal › Article › peer-review

Abstract

The poor prognosis of glioblastoma (GBM) patients is attributed mainly to abundant neovascularization and presence of glioblastoma stem cells (GSCs). GSCs are preferentially localized to the perivascular niche to maintain stemness. However, the effect of abnormal communication between endothelial cells (ECs) and GSCs on GBM progression remains unknown. Here, we reveal that ECs-derived SEMA3G, which is aberrantly expressed in GBM patients, impairs GSCs by inducing c-Myc degradation. SEMA3G activates NRP2/PLXNA1 in a paracrine manner, subsequently inducing the inactivation of Cdc42 and dissociation of Cdc42 and WWP2 in GSCs. Once released, WWP2 interacts with c-Myc and mediates c-Myc degradation via ubiquitination. Genetic deletion of Sema3G in ECs accelerates GBM growth, whereas SEMA3G overexpression or recombinant SEMA3G protein prolongs the survival of GBM bearing mice. These findings illustrate that ECs play an intrinsic inhibitory role in GSCs stemness via the SMEA3G-c-Myc distal regulation paradigm. Targeting SEMA3G signaling may have promising therapeutic benefits for GBM patients.

Original language	English
Journal	Cell Death and Differentiation
DOIs	https://doi.org/10.1038/s41418-025-01534-3
Publication status	Accepted/In press - 2025

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10.1038/s41418-025-01534-3

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Min, P. X., Feng, L. L., Zhang, Y. X., Jiang, C. C., Zhang, H. Z., Chen, Y., Fukunaga, K., Liu, F., Zhang, Y. J., Sasaki, T., Qian, X., Horimoto, K., Jiang, J. D., Lu, Y. M., & Han, F. (Accepted/In press). Endothelial cells-derived SEMA3G suppresses glioblastoma stem cells by inducing c-Myc degradation. Cell Death and Differentiation. https://doi.org/10.1038/s41418-025-01534-3

@article{a7685fd3ea5142debec1b9f419180f22,

title = "Endothelial cells-derived SEMA3G suppresses glioblastoma stem cells by inducing c-Myc degradation",

abstract = "The poor prognosis of glioblastoma (GBM) patients is attributed mainly to abundant neovascularization and presence of glioblastoma stem cells (GSCs). GSCs are preferentially localized to the perivascular niche to maintain stemness. However, the effect of abnormal communication between endothelial cells (ECs) and GSCs on GBM progression remains unknown. Here, we reveal that ECs-derived SEMA3G, which is aberrantly expressed in GBM patients, impairs GSCs by inducing c-Myc degradation. SEMA3G activates NRP2/PLXNA1 in a paracrine manner, subsequently inducing the inactivation of Cdc42 and dissociation of Cdc42 and WWP2 in GSCs. Once released, WWP2 interacts with c-Myc and mediates c-Myc degradation via ubiquitination. Genetic deletion of Sema3G in ECs accelerates GBM growth, whereas SEMA3G overexpression or recombinant SEMA3G protein prolongs the survival of GBM bearing mice. These findings illustrate that ECs play an intrinsic inhibitory role in GSCs stemness via the SMEA3G-c-Myc distal regulation paradigm. Targeting SEMA3G signaling may have promising therapeutic benefits for GBM patients.",

author = "Min, \{Peng Xiang\} and Feng, \{Li Li\} and Zhang, \{Yi Xuan\} and Jiang, \{Chen Chen\} and Zhang, \{Hong Zhen\} and Yan Chen and Kohji Fukunaga and Fang Liu and Zhang, \{Yu Jie\} and Takuya Sasaki and Xu Qian and Katsuhisa Horimoto and Jiang, \{Jian Dong\} and Lu, \{Ying Mei\} and Feng Han",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

year = "2025",

doi = "10.1038/s41418-025-01534-3",

language = "English",

journal = "Cell Death and Differentiation",

issn = "1350-9047",

publisher = "Springer Nature",

}

TY - JOUR

T1 - Endothelial cells-derived SEMA3G suppresses glioblastoma stem cells by inducing c-Myc degradation

AU - Min, Peng Xiang

AU - Feng, Li Li

AU - Zhang, Yi Xuan

AU - Jiang, Chen Chen

AU - Zhang, Hong Zhen

AU - Chen, Yan

AU - Fukunaga, Kohji

AU - Liu, Fang

AU - Zhang, Yu Jie

AU - Sasaki, Takuya

AU - Qian, Xu

AU - Horimoto, Katsuhisa

AU - Jiang, Jian Dong

AU - Lu, Ying Mei

AU - Han, Feng

PY - 2025

Y1 - 2025

N2 - The poor prognosis of glioblastoma (GBM) patients is attributed mainly to abundant neovascularization and presence of glioblastoma stem cells (GSCs). GSCs are preferentially localized to the perivascular niche to maintain stemness. However, the effect of abnormal communication between endothelial cells (ECs) and GSCs on GBM progression remains unknown. Here, we reveal that ECs-derived SEMA3G, which is aberrantly expressed in GBM patients, impairs GSCs by inducing c-Myc degradation. SEMA3G activates NRP2/PLXNA1 in a paracrine manner, subsequently inducing the inactivation of Cdc42 and dissociation of Cdc42 and WWP2 in GSCs. Once released, WWP2 interacts with c-Myc and mediates c-Myc degradation via ubiquitination. Genetic deletion of Sema3G in ECs accelerates GBM growth, whereas SEMA3G overexpression or recombinant SEMA3G protein prolongs the survival of GBM bearing mice. These findings illustrate that ECs play an intrinsic inhibitory role in GSCs stemness via the SMEA3G-c-Myc distal regulation paradigm. Targeting SEMA3G signaling may have promising therapeutic benefits for GBM patients.

AB - The poor prognosis of glioblastoma (GBM) patients is attributed mainly to abundant neovascularization and presence of glioblastoma stem cells (GSCs). GSCs are preferentially localized to the perivascular niche to maintain stemness. However, the effect of abnormal communication between endothelial cells (ECs) and GSCs on GBM progression remains unknown. Here, we reveal that ECs-derived SEMA3G, which is aberrantly expressed in GBM patients, impairs GSCs by inducing c-Myc degradation. SEMA3G activates NRP2/PLXNA1 in a paracrine manner, subsequently inducing the inactivation of Cdc42 and dissociation of Cdc42 and WWP2 in GSCs. Once released, WWP2 interacts with c-Myc and mediates c-Myc degradation via ubiquitination. Genetic deletion of Sema3G in ECs accelerates GBM growth, whereas SEMA3G overexpression or recombinant SEMA3G protein prolongs the survival of GBM bearing mice. These findings illustrate that ECs play an intrinsic inhibitory role in GSCs stemness via the SMEA3G-c-Myc distal regulation paradigm. Targeting SEMA3G signaling may have promising therapeutic benefits for GBM patients.

UR - https://www.scopus.com/pages/publications/105008400342

UR - https://www.scopus.com/inward/citedby.url?scp=105008400342&partnerID=8YFLogxK

U2 - 10.1038/s41418-025-01534-3

DO - 10.1038/s41418-025-01534-3

M3 - Article

AN - SCOPUS:105008400342

SN - 1350-9047

JO - Cell Death and Differentiation

JF - Cell Death and Differentiation

ER -

Endothelial cells-derived SEMA3G suppresses glioblastoma stem cells by inducing c-Myc degradation

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